EP3858388B1 - T-zellen mit chimärem antigenrezeptor (car) als therapeutische eingriffe bei gvhd - Google Patents

T-zellen mit chimärem antigenrezeptor (car) als therapeutische eingriffe bei gvhd Download PDF

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EP3858388B1
EP3858388B1 EP21154942.3A EP21154942A EP3858388B1 EP 3858388 B1 EP3858388 B1 EP 3858388B1 EP 21154942 A EP21154942 A EP 21154942A EP 3858388 B1 EP3858388 B1 EP 3858388B1
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cells
car
human
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human patient
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EP3858388A1 (de
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Bruce R. Blazar
Ryan P. FLYNN
Christopher A. PENNELL
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University of Minnesota
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/462—Cellular immunotherapy characterized by the effect or the function of the cells
    • A61K39/4621—Cellular immunotherapy characterized by the effect or the function of the cells immunosuppressive or immunotolerising
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631—Chimeric Antigen Receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/46434—Antigens related to induction of tolerance to non-self
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464402—Receptors, cell surface antigens or cell surface determinants
    • A61K39/464403—Receptors for growth factors
    • A61K39/464404—Epidermal growth factor receptors [EGFR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464402—Receptors, cell surface antigens or cell surface determinants
    • A61K39/464411—Immunoglobulin superfamily
    • A61K39/464412—CD19 or B4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2207/00—Modified animals
    • A01K2207/15—Humanized animals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/035—Animal model for multifactorial diseases
    • A01K2267/0387—Animal model for diseases of the immune system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/31—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterized by the route of administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K39/46
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the dose, timing or administration schedule
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/10041—Use of virus, viral particle or viral elements as a vector
    • C12N2740/10043—Use of virus, viral particle or viral elements as a vector viral genome or elements thereof as genetic vector

Definitions

  • treatment refers to reversing, alleviating, or inhibiting the progress of an autoimmune or alloimmune disease, or one or more symptoms associated with such an autoimmune or alloimmune disease. It would be understood that the particular therapeutic endpoint(s) that determines whether or not treatment has been achieved (e.g., whether or not a patient has been treated) will depend upon whether the patient suffers from an autoimmune disease or an alloimmune disease as well as the particular type of autoimmune or alloimmune disease.
  • a 24-well tissue culture plate was coated with 100 ⁇ g/mL RetroNectin in PBS. Samples were incubated at room temperature for 3 hr OR overnight at 4°C.
  • T cell counts were obtained daily or every other day to maintain a T cell concentration of 1-2 x 10 ⁇ 6 cells/mL for optimal expansion and viability. 1-2 wells per condition were reserved to use for counting and not for eventual ACT.
  • transduction efficiency of T cells was analyzed by FACS. Cells were harvested as appropriate for functional assays.
  • transduction efficiency of T cells was analyzed by FACS. Optimal efficiency was generally observed between day 6 and day 7. Cells were harvested for functional assays, typically on the day of adoptive transfer.
  • TBL12.huCD19 The human CD19 gene, along with reporter genes encoding green fluorescent protein (GFP) and luciferase, were introduced into a mouse B cell tumor called TBL12. This derivative was designated TBL12.huCD19. Both the parental TBL12 and the derivative TBL12.huCD19 lines express mouse CD19, but only the derivative line, TBL12.huCD19, expresses human CD19 and GFP. Both of these proteins are detectable by flow cytometry.
  • GFP green fluorescent protein
  • the anti-human CAR T cells specifically kill human CD19-bearing tumor targets in vitro.
  • Anti-human CD19 CAR T cells (0.3 x 10 ⁇ 6), or control T cells transduced with a retrovirus encoding the reporter protein GFP (0.3 x 10 ⁇ 6), were injected intravenously into huCD19TG +/- mice. After four days, mice were euthanized and their spleens removed and frozen in optimal cutting temperature tissue medium. Thin (10 ⁇ m) sections were cut on a cryostat, fixed, and stained with fluorophore-conjugated antibodies specific for endogenous B cells or the adoptively transferred T cells. Tissue images were captured by confocal microscopy at 20X magnification.
  • Figure 4A shows massive accumulation of CAR T cells (green) in the spleen of a huCD19TG +/- mouse, and no detectable endogenous B cells (red).
  • Figure 4B shows the spleen from a control huCD19TG +/- mouse injected with T cells treated identically to the CAR T cells except the retrovirus encoded GFP, not the anti-human CD19 CAR. Endogenous B cells (red) are plentiful and the infiltrating T cells (green) are detectable but have not expanded to the extent seen in Figure 4A .
  • the experimental results shown in Figures 4A and 4B demonstrate that CAR T cells engineered and expanded ex vivo kill human CD19 + B cells when transferred into huCD19TG +/- mice.
  • the huCD19TG +/- model is suitable to assess on-target/off-tumor toxicity.
  • Tregs were purified from LN + SP of 115 wild type (WT) B6 mice using EasySep CD4 negative selection and CD25 positive selection. Analysis showed that the resulting product contained 99.9% CD4+ CD25+. Once purified, Tregs were activated for 4 days using plate-bound anti-CD3+ (2 ⁇ g) and CD28+ antibodies (4 ⁇ g).
  • Tregs were then transduced with either CAR hCD19-EGFR or Control RV-EGFR using routine methods. On day 5 post-transduction efficiency was low, so cells were transduced a second time using the same methods. On day 7 post-transduction, transduction efficiency was about 30% for both CAR hCD19 Treg cells and control Treg cells. At day 7 post-transduction, the purity was >93% for both groups, and the yield was 26.75 million CAR hCD19 Treg cells and 22.5 million control Treg cells.
  • Figure 5 shows pulmonary function after 60 days;
  • Figure 5A shows resistance of mice without or with chronic GVHD, and chronic GVHD mice treated on day 28 with CAR-T cells or GFP-T cells. High resistance indicative of chronic GVHD was reversed by CAR-T cells but not GFP-T cells;
  • Figure 5B shows elastance of transplantation mice without or with chronic GVHD, and chronic GVHD mice treated on day 28 with CAR-T cells or GFP-T cells. High elastance indicative of chronic GVHD was reversed by CAR-T cells but not GFP-T cells;
  • Figure 5C shows low compliance of transplantation mice without or with chronic GVHD, and chronic GVHD mice treated on day 28 with CAR-T cells or GFP T-cells. Low compliance indicative of chronic GVHD was reversed by CAR-T cells but not GFP-T cells.
  • Figure 6 shows that hCD19+ cells persist in recipient mice at 4 days post-transplantation (from CD4- lymphocytes).
  • Figure 7 shows that the addition of CAR CD19 Treg cells significantly improved survival of transplanted mice compared to mice transplanted with only bone marrow and T cells or mice transplanted with bone marrow and control Treg cells.
  • Figure 8 shows that the weight loss of transplanted mice were similar, irrespective of whether T cells and/or CAR CD 19 Treg cells were delivered to the mice.
  • Figure 9 shows that mice transplanted with bone marrow, T cells and CAR CD 19 Treg cells exhibited a better clinical score than mice transplanted with bone marrow alone and a clinical score similar to mice transplanted with bone marrow and T cells or bone marrow, T cells and control Treg cells.
  • CAR-T cells, but not GFP-T cells caused weight loss and clinical findings consistent with a cytokine release syndrome in CD19 heterozygous mice, unexpectedly, neither CAR-T cells nor GFP-T cells adversely affected survival.

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Claims (10)

  1. Eine pharmazeutische Zusammensetzung zur Verwendung bei der Behandlung von Graft-vs-Host-Disease (GVHD) in einem menschlichen Patienten, wobei die pharmazeutische Zusammensetzung eine therapeutisch effektive Menge einer Population von modifizierten humanen regulatorischen T-Zellen (Treg-Zellen) umfasst, wobei die humanen Treg-Zellen modifiziert sind, um eine Nukleinsäuresequenz zu exprimieren, die ein chimäres Antigenrezeptor (CAR) -konstrukt kodiert, wobei das CARkonstrukt eine Antigenbindedomäne umfasst, wobei die Antigenbindedomäne spezifisch ist für CD19.
  2. Die Zusammensetzung zur Verwendung nach Anspruch 1, wobei die Treg-Zellen autolog in Bezug auf den menschlichen Patienten sind.
  3. Die Zusammensetzung zur Verwendung nach Anspruch 1, wobei die Treg-Zellen allogen in Bezug auf den menschlichen Patienten sind.
  4. Die Zusammensetzung zur Verwendung nach einem der vorhergehenden Ansprüche, wobei die modifizierten Treg-Zellen in vivo in dem menschlichen Patienten replizieren.
  5. Die Zusammensetzung zur Verwendung nach einem der vorhergehenden Ansprüche, wobei die modifizierten Treg-Zellen Memory T-Zellen in dem menschlichen Patienten gegen B-Zellen, Plasmazellen oder Plasmablasten bilden, die einen Liganden exprimieren, der von der Antigenbindedomäne erkannt wird.
  6. Die Zusammensetzung zur Verwendung nach einem der vorhergehenden Ansprüche, wobei die effektive Menge der Treg-Zellen zwischen etwa 104 und etwa 109 Zellen pro kg Körpergewicht des menschlichen Patienten ist.
  7. Die Zusammensetzung zur Verwendung nach einem der vorhergehenden Ansprüche, wobei die effektive Menge von Treg-Zellen zwischen etwa 105 und etwa 106 Zellen pro kg Körpergewicht des menschlichen Patienten ist.
  8. Die Zusammensetzung zur Verwendung nach einem der vorhergehenden Ansprüche, wobei die Antigenbindedomäne ein Antikörper oder ein Antigen-bindendes Fragment davon ist.
  9. Die Zusammensetzung zur Verwendung nach Anspruch 8, wobei das Antigen-bindende Fragment ein Fab oder ein scFv ist.
  10. Die Zusammensetzung zur Verwendung nach einem der vorhergehenden Ansprüche, wobei die modifizierten Treg-Zellen intravenös an den menschlichen Patienten zu verabreichen sind.
EP21154942.3A 2015-09-28 2016-09-28 T-zellen mit chimärem antigenrezeptor (car) als therapeutische eingriffe bei gvhd Active EP3858388B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201562233908P 2015-09-28 2015-09-28
EP16852441.1A EP3355937A4 (de) 2015-09-28 2016-09-28 T-zellen mit chimärem antigenrezeptor (car) als therapeutische eingriffe bei auto- und allo-immunität
PCT/US2016/054076 WO2017058850A1 (en) 2015-09-28 2016-09-28 Chimeric antigen receptor (car) t cells as therapeutic interventions for auto- and allo-immunity

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EP3858388B1 true EP3858388B1 (de) 2024-07-03

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EP21154942.3A Active EP3858388B1 (de) 2015-09-28 2016-09-28 T-zellen mit chimärem antigenrezeptor (car) als therapeutische eingriffe bei gvhd

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US (1) US20180264038A1 (de)
EP (2) EP3355937A4 (de)
JP (2) JP2018534264A (de)
CN (1) CN108348620A (de)
HK (1) HK1258726A1 (de)
WO (1) WO2017058850A1 (de)

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JP2022023194A (ja) 2022-02-07
JP2018534264A (ja) 2018-11-22
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HK1258726A1 (zh) 2019-11-15
CN108348620A (zh) 2018-07-31

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